Fundamental gaps exist in our understanding of how HIV-1 may interact with the pathogenesis of Alzheimer's disease (AD), and determining its underlying mechanisms is set as our long-term goal. The objective of the proposed studies is to determine molecular mechanisms whereby transactivator of transcription (Tat), a HIV-1 viral protein that continues to be implicated in the pathogenesis of HIV-1 associated neurocognitive disorder (HAND) and has recently been implicated in the development of AD-like pathology, increases neuronal A? generation. Our central hypothesis is that Tat increases intraneuronal A? production by promoting APP internalization and elevating endolysosome pH. Guided by our preliminary findings, this novel, untested hypothesis will be tested by pursuing two specific aims: (1) Determine mechanisms whereby Tat promotes APP internalization, thus enhancing APP processing in favor of A? production. (2) Determine mechanisms whereby Tat elevates endolysosome pH, thus enhancing BACE-1 activity in favor of A? production. Results from work proposed in Aim #1 are expected to demonstrate that LRP-1 is responsible for HIV-1 protein- induced increases in APP internalization, and that siRNA knockdown of LRP-1 prevents HIV-1 protein-induced intraneuronal A? production. Results from Aim #2 are expected to demonstrate that a proton-dependent peptide transporter, Pept2, is responsible for Tat-induced elevation of endolysosome pH, and that siRNA knockdown of Pept2 prevents Tat-induced elevation of endolysosome pH, increased endolysosome accumulation of BACE-1, enhanced BACE-1 activity, and increased intraneuronal A? production. Such results are expected to provide us with new targets and rationale for preventative and therapeutic interventions against HAND and AD. Thus, the outcome of the proposed studies could have a substantial impact economically, socially and clinically.